Pyrimidine derivatives for enhancing antitumor activity

ABSTRACT

2,4-diaminopyrimidine derivatives as potentiators of chemotherapeutic agents in the treatment of cancer.

This application is the 371 of PCT/US92/02434, filed Mar. 30, 1992.

BACKGROUND OF THE INVENTION

This invention relates to 2,4-diaminopyrimidines and their use assensitizers of tumor cells to anticancer agents.

In cancer chemotherapy the effectiveness of anticancer drugs is oftenlimited by the resistance of tumor cells. Some tumors such as of thecolon, pancreas, kidney and liver are generally innately resistant, andother responding tumors often develop resistance during the course ofchemotherapy. The phenomena of multidrug resistance (MDR) ischaracterized by the tumor cell's cross-resistance to structurallyunrelated drugs. The drugs which are the target of resistance includeadriamycin, daunomycin, vinblastine, vincristine, actinomycin D andetoposide. The resistance cells are often associated withover-expression of the mdr1 gene. This gene product is a family of140-220 kd trans-membrane phosphoglycoprotein (P-glycoprotein) whichfunctions as an ATP-dependent efflux pump. Thus, it has been postulatedthat this efflux mechanism keeps the intracellular level of theanticancer drug low, allowing the tumor cells to survive.

In recent years various substances such as verapamil, nifedipine anddiltiazem have been used in in vitro experimental systems to reverse theMDR phenomena. More recently some of these agents have been testedclinically as MDR reversing agents. Little efficacy has been observedwith verapamil or trifluoroperazine. Thus, there is a need for aneffective MDR reversing agent.

Fukazawa, et al. describes a series of heterocyclic compounds (EPApplication No. 89310235.0) useful as anticancer-drug reinforcingagents. This same utility is also claimed for a series of pteridinederivatives (EP Application No. 89117610.9).

Tomino, et al. (EP Application No. 89313595.4) claims a series ofpyrimidines, including 2,4-diaminopyrimidines, useful in the treatmentof neurological diseases.

A series of 2,4,6-triaminopyrimidine-N-oxides (U.S. Pat. No. 4,945,093)are described as being useful for promoting hair growth.

SUMMARY OF THE INVENTION

The compounds of the present invention are of the formula ##STR1## andthe pharmaceutically acceptable salts thereof wherein M is hydrogen,alkoxy of one to three carbon atoms, alkyl of one to three carbon atomsor benzyl optionally substituted by one or two alkoxy substituents eachhaving one to three carbon atoms, chloro, fluoro, amino, alkylamino ofone to three carbon atoms, dialkylamino of two to six carbon atoms ortrifluoromethyl; M¹ is hydrogen, amino, alkylamino of one to threecarbon atoms, dialkylamino of two to six carbon atoms, alkyl of one tothree carbon atoms, fluoro or chloro; R₁ is aralkyl of the formula##STR2## wherein n is an integer of 0 or 1, W is O, S or a chemicalbond, A is alkylene of one to four carbon atoms, Y and Y¹ are eachhydrogen, alkyl of one to three carbon atoms, alkoxy of one to threecarbon atoms, fluoro, chloro, trifluoromethyl, amino, alkylamino of oneto three carbon atoms or dialkylamino of two to six carbon atoms and Yand Y¹ when taken together are ethylenedioxy or methylenedioxy; R₂ ishydrogen or alkyl of one to eight carbon atoms; R₁ and R₂ when takentogether with the nitrogen atom to which they are attached form a moietyof the formula ##STR3## where R₅ is hydrogen, alkyl of one to threecarbon atoms or dialkoxyphenylalkyl said alkoxy having one to threecarbon atoms and said alkyl having from one to three carbon atoms, Q andQ¹ are each hydrogen, alkyl of one to three carbon atoms, alkoxy of oneto three carbon atoms, fluoro, chloro, trifluoromethyl, amino,alkylamino of one to three carbon atoms or dialkylamino of two to sixcarbon atoms and Q and Q¹ taken together are methylenedioxy orethylenedioxy; R₃ is aralkyl of the formula ##STR4## where m is aninteger of 0 or 1, Z is 0, S or a chemical bond, B is alkylene of one tofour carbon atoms, X and X¹ are each hydrogen, alkyl of one to threecarbon atoms, alkoxy of one to three carbon atoms, fluoro, chloro,trifluoromethyl, amino, alkylamino of one to three carbon atoms ordialkylamino of two to six carbon atoms and X and X¹ taken together aremethylenedioxy or ethylenedioxy; R₄ is hydrogen or alkyl of one to fourcarbon atoms; and R₃ and R₄ when taken together with the nitrogen atomto which they are attached form a moiety of the formula ##STR5## whereR₆ is hydrogen or dialkoxybenzyl said alkoxy having one to three carbonatoms, P and P¹ are each hydrogen, alkyl of one to three carbon atoms,alkoxy of one to three carbon atoms, fluoro, chloro, trifluoromethyl,amino, alkylamino of one to three carbons atoms or dialkylamino of twoto six carbon atoms, or P and P¹ when taken together are methylenedioxyor ethylenedioxy.

A preferred group of compounds are those wherein M¹ is hydrogen or alkylof one to three carbon atoms, R₁ and R₂ taken together with the nitrogento which they are attached are ##STR6## where Q is 6-methoxy, Q¹ is7-methoxy and R₃ and R₄ taken together with the nitrogen to which theyare attached are ##STR7## where P is 6-methoxy and P¹ is 7-methoxy.Especially preferred within this group are the compounds where M ishydrogen, M¹ is hydrogen, R₅ is 3,4-dimethoxybenzyl and R₆ is3,4-dimethoxybenzyl and where M is hydrogen, M¹ is hydrogen, R₅ is3,4-dimethoxybenzyl and R₆ is hydrogen.

A second group of preferred compounds are those where M isdialkoxybenzyl, M¹ is hydrogen, R₁ and R₂ taken together with thenitrogen to which they are attached are ##STR8## where Q is 6-methoxyand Q¹ is 7-methoxy, R₃ is aralkyl of the formula ##STR9## where m is 0,Z is a chemical bond and B is ethylene and R₄ is hydrogen. Especiallypreferred within this group are the compounds where M is3,4-dimethyoxybenzyl, R₅ is hydrogen, X is 2-chloro and X¹ is hydrogen,where M is 3,4-dimethoxybenzyl, R₅ is 3,4-dimethoxybenzyl, X is 2-chloroand X¹ is hydrogen.

A third group of preferred compounds are those wherein M is hydrogen, M¹is hydrogen or alkyl of one to three carbon atoms, R₃ is aralkyl of theformula ##STR10## where m is 0, Z is a chemical bond and B is ethylene,R₄ is hydrogen and R₁ and R₂ taken together with the nitrogen to whichthey are attached are ##STR11## where Q is 6-methoxy and Q¹ is7-methoxy. Especially preferred within this group are compounds where M¹is methyl, X is 3-methoxy, X¹ is 4-methoxy and R₅ hydrogen, where M¹ ishydrogen, X is 2-methoxy, X¹ is 3-methoxy and R₅ is 3,4-dimethoxybenzyl,where M¹ is hydrogen, X is 2-chloro, X¹ is hydrogen and R₅ is3,4-dimethoxybenzyl, where M¹ is hydrogen, X and X¹ together are3,4-methylenedioxy and R₅ is 3,4-dimethoxybenzyl and where M¹ is methyl,X is 2-chloro, X¹ is hydrogen and R₅ is 3,4-dimethoxybenzyl.

The present invention also includes a method of inhibiting aP-glycoprotein in a mammal in need of such treatment which comprisesadministering to said mammal a P-glycoprotein inhibiting amount of acompound of formula I. Preferred is the method where the mammal is ahuman suffering from cancer and said compound is administered before,with or after the administration to said human of an anticancereffective amount of a chemotherapeutic agent.

Also included is a pharmaceutical composition for administration to amammal which comprises a P-glycoprotein inhibiting amount of a compoundof formula I, a pharmaceutically acceptable carrier and, optionally, ananticancer effective amount of a chemotherapeutic agent.

As previously indicated, the compounds of formula (I) formpharmaceutically acceptable acid addition salts. Said pharmaceuticallyacceptable acid addition salts include, but are not limited to, thosewith HCl, HBr, HNO₃, H₂ SO₄ ; H₃ PO₄, CH₃ SO₃ H, p-CH₃ C₆ H₄ SO₃ H, CH₃CO₂ H, gluconic acid, tartaric acid, maleic acid and succinic acid. Inthe case of those compounds of the formula (I) which contain a furtherbasic nitrogen, it will, of course, be possible to form diacid additionsalts (e.g., the dihydrochloride) as well as the usual monoacid additionsalt.

As one skilled in the art recognized, compounds of formula I have thepotential for containing asymmetric carbon atoms. All these potentialisomers are considered within the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the present invention are prepared with the reaction of a2,4-dichloropyrimidine with an equivalent of an appropriate amine, R₁ R₂NH, followed by the reaction of the product, a2-chloro-4-aminopyrimidine derivative, with a second equivalent of anappropriate amine, R₃ R₄ NH.

In a more detailed description of the procedure, one molar equivalent ofan optionally substituted 2,4-dichloropyrimidine and one molarequivalent of a tertiary amine-acid scavenger, such as triethylamine,N-methylmorpholine or diethylisopropylamine and one molar equivalent ofan amine, R₁ R₂ NH, are combined in an anhydrous solvent such asdimethylacetamide, dioxane, methylene chloride or N-methyl-2-pyrrolidoneand maintained at from 0° C. to about 25° C. for a period of 1 to 48hours.

The reaction mixture can be filtered and the filtrate concentrated todryness in vacuo, or the reaction mixture can be quenched in water andthe intermediate product either filtered or extracted with a waterimmiscible solvent such as methylene chloride or ethyl acetate. Removalof the extracting solvent provides the desired product. Frequently, theresidual can be induced to crystallize by trituration with an organicsolvent, and further purified by recrystallization or columnchromatography.

The second step of the sequence leading to the products of the presentinvention consists of combining one molar equivalent of the appropriate2-chloro-4-aminopyrimidine with either two molar equivalents of anamine, R₃ R₄ NH, or one equivalent of said amine and one equivalent of atertiary amine-acid scavenger as described above in a reaction-inertsolvent such as ethoxyethoxyethanol, butanol, amyl alcohol orcyclohexanol for a period of 5 minutes to several hours at reactiontemperatures of 100°-200° C.

The reaction mixture can be cooled to room temperature and treated witha 1-N solution of an appropriate acid, such as hydrochloric acid to givea precipitate of the desired product as the hydrochloride salt. Otheracids would give the corresponding acid addition salt. In instanceswhere the acid addition salt does not precipitate the free base productcan be isolated by chromatographing the crude material on silica gelusing an eluant such as chloroform, ethyl acetate, diethyl ether,methanol, methylene chloride, ethanol or mixtures thereof andsubsequently converted to the acid addition salt product. The productsare isolated by removing the eluting solvents in vacuo. Purification ofthe product can be done by recrystallization.

Generation of the free base from an acid addition salt can readily becarried out by treating an aqueous solution or suspension of the saltwith at least one equivalent of an organic or inorganic base followed byextraction of the free base product with a water immiscible solvent suchas ethyl acetate or methylene chloride. Removal of the solvent gives thedesired base.

Compounds of formula I are inhibitors of the functions ofP-glycoprotein, particularly human mdr 1 protein or P-glycoproteinrelated and membrane associate proteins which are participating in thetransport of xenobiotics or proteins across membranes e.g., cellmembranes of eukariotic and proeukariotic origin e.g., pmfdr, howevernot exclusive or restricted to these examples.

Compounds enclosed in general formula I are useful in combinationchemotherapy of cancer, malaria, viral infections such as AIDS, intherapy of septic shock syndrome or inflammation and may be useful inenhancing the tissue penetration of drugs where the penetration of thesexenobiotics is limited due to the presence of P-glycoprotein orP-glycoprotein related functional proteins. Compounds of formula Iincrease the activity/efficacy of adriamycin, daunomycin,epipodophyllotoxin congoners, actinomycin D, emetin, vincristin,vinblastin, chloroquine, anthracyclin antibiotics and of drugs which arestructurally and functionally related to the above mentioned examples,in particular when the activity of these drugs has been shown to belimited due to the presence and function of P-glycoprotein, e.g. humanmdr 1 protein or P-glycoprotein related proteins.

The compounds of the present invention are evaluated as potentiators ofchemotherapeutic agents using a Cellular Drug Retention Assay. Thisassay was designed to study the effect of compounds on cellularretention of radiolabeled drug. In this case 14C-adriamycin retention bymultidrug resistant human carcinoma cells, KBV1, is measured.

KBV1 cells are routinely grown in tissue culture as monolayers in DMEMhigh glucose medium containing 1 μg/ml vinblastine 10% heat inactivatedfetal calf serum and supplemented with Glutamine, Pen-Strep andGaramycin.

The assay protocol (described below) should be applicable, with minormodifications, to a wide variety of cell lines grown in tissue culture.

Assay Protocol:

(1) Seed replicate 6-well tissue culture plates with 1.2×10E6 cells per2 ml per well in absence of Vinblastine;

(2) Incubate 24 hrs at 37° C. in a humidified incubator (5% CO₂);

(3) Aspirate off the spent media and overlay monolayers with 2 ml/wellof fresh medium that is 2 μM in Adriamycin (2 μM unlabeledAdriamycin+20000 cpm of ¹⁴ C-Adriamycin) and the test agent atconcentrations varying from 0 to 100 μM;

(4) Following incubation for 3 hours at 37° C. in a humidifiedincubator, remove media and wash monolayers twice with 2 ml of ice-coldbuffered saline;

(5) Detach monolayers using 0.5 ml of trypsin/EDTA, collect detachedcells and transfer to scintillation vial. Rinse wells once with 0.5 mlof buffered saline and add to the same vial containing cells;

(6) Add 5 ml of Beckman Ready-Sare™ scintillation fluid to vial, vortexand determine radioactivity per sample using a scintillation counter (10minutes per sample);

(7) For background control: pre-incubate monolayers at 4° C. for 15minutes then remove media and add fresh ice-cold media containingAdriamycin (see step 3). Following incubation for 3 hours at 4° C.remove media and wash monolayers twice with 2 ml ice-cold bufferedsaline, then proceed as in step 5;

(8) Results are expressed as T/C and ED3x values as defined below:

T/C=pmoles Adr per 10E6 cells treated with test agent/pmoles Adr per10E6 untreated cells

ED3x=concentration of test agent that produces a 3 fold increase incellular accumulation of radiolabeled Adr, i.e. T/C=3.

Calculations

Specific cpm=[sample cpm-background cpm]

Specific activity=[cpm/total conc. of Adr]

pmoles Adr=[specific cpm/specific activity]

pmoles Adr per 10E6 cells=[(pmoles Adr per well/number of cells perwell)×10E6 cells]

As previously mentioned compounds of the present invention and saltsthereof are useful in potentiating the anticancer effects ofchemotherapeutic agents. Such agents can include adriamycin, daunomycin,aclacinomycin A, actinomycin C, actinomycin D, mithramycin, tomaymycin,vinblastine, maytansine, bruceantin, homoharrintonin, anguindin,neocarzinostatin, mitomycin C and anthramycin.

The compounds of the present invention can be administered with, 24hours before or up to 72 hours after the administration of thechemotherapeutic agents. When administered with said agents, they can betaken either separately or coadministered in the same formulation.

The compounds of the present invention whether taken separately or incombination with an anticancer agent, are generally administered in theform of pharmaceutical compositions comprising at least one of thecompounds of formula I and optionally a chemotherapeutic agent, togetherwith a pharmaceutically acceptable vehicle or diluent. Such compositionsare generally formulated in a conventional manner utilizing solid orliquid vehicles or diluents as appropriate to the mode of desiredadministration: for oral administration, in the form of tablets, hard orsoft gelatin capsules, suspensions, granules, powders and the like, and,for parenteral administration, in the form of injectable solutions orsuspensions, and the like.

For use in the potentiation of anticancer agents in a mammal, includingman, a compound of formula I is given in an amount of about 0.5-100mg/kg/day, in single or divided doses. A more preferred dosage range is2-50 mg/kg/day, although in particular cases, at the discretion of theattending physician, doses outside the broader range may be required.The preferred route of administration is generally oral, but parenteraladministration (e.g. intramuscular, intravenous, intradermal) will bepreferred in special cases, e.g., where oral absorption is impaired asby disease, or where the patient is unable to swallow.

The present invention is illustrated by the following examples, but isnot limited to the details or scope thereof.

EXAMPLE 1

2-(2-Chlorophenethylamino)-4-(1,2,3,4-tetrahydro-6,7-dimethoxyisoquinol-2-yl)-5-(3,4-dimethoxybenzyl)-pyrimidine(M=3,4-(CH₃ O)₂ C₆ H₃ CH₂ --; M¹ =H; R₁ R₂ N=1,2,3,4-tetrahydro-6,7-(CH₃O)₂ -isoquinol-2-yl; R₃ =2-ClC₆ H₄ (CH₂)₂ --; and R₄ =H)

A. 5-(3,4-Dimethoxybenzyl)uracil

A solution of 5.0 g of 5-hydroxymethyluracil, 150 ml of veratrole and0.5 ml of concentrated hydrochloric acid was heated at 140° C. for onehour. The precipitate was filtered, washed with ether and recrystallizedfrom hot methanol, 6.85 g, M⁺ 263.20.

B. 2,4-Dichloro-5-(3,4-dimethoxybenzyl)pyrimidine

A mixture of 4.7 g of the product of Example 1A and 125 ml of phosphorusoxychloride was heated to reflux overnight. The excess phosphorusoxychloride was removed in vacuo and the residue poured into ice water.The aqueous was extracted with methylene chloride and the extractscombined and dried over sodium sulfate. The residue, after removal ofthe methylene chloride, was chromatographed on silica gel (methylenechloride) to give 4.92 g of the desired intermediate, M⁺ 299.0.

C.2-Chloro-4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(3,4-dimethoxybenzyl)pyrimidine

A solution of 2.0 g of the compound of Example 1B, 1.54 g of6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride and 1.73 g ofdiisopropylethylamine in 125 ml of dioxane was heated to refluxovernight. The solvent was removed in vacuo and the residuechromatographed on silica gel (4% ethyl acetate-methylene chloride) togive 2.27 g of product, M⁺ 456.10.

D.2-(2-Chlorophenethylamino)-4-(1,2,3,4-tetrahydro-6,7-dimethoxyisoquinol-2-yl)-5-(3,4-dimethoxybenzyl)pyrimidine

A mixture of 300 mg of the product of Example 1C, 102 mg of2-chlorophenethylamine and 85 mg of diisopropylethylamine in 1 ml of2-(2-ethoxyethoxy)ethanol was heated to 160° C. for two hours. Thesolvent was removed in vacuo and the residue chromatographed on silicagel (2% methanol-methylene chloride) to give 230 mg of product, m.p.140°-141° C., M⁺ 575.30.

EXAMPLES 2-16

Starting with the appropriate reagents and employing the procedures ofExample 1, the following compounds were prepared: ##STR12##

Example 2: M=H; M¹ =6-CH₃ ; R₅ =H; Q¹ =6-CH₃ O; Q² =7-CH₃ O; R₃=2,3-(CH₃ O)₂ C₆ H₃ (CH₂)--; and R₄ =H; m.p. 224°-226.5° C., M⁺ 465.00.

Example 3: M, M¹ =H; R₅ =H; Q¹ =6-CH₃ O; Q² =7-CH₃ O; R₃ NR₄ = ##STR13##m.p. 151°-153° C., M⁺ 613.20.

Example 4: M, M¹ =H; R₅ =3,4-(CH₃ O)₂ C₆ H₃ CH₂ --; Q¹ =6-CH₃ O; Q²=7-CH₃ O; R₃ NR₄ = ##STR14## m.p. 138°-142° C., M⁺ 763.40.

Example 5: M, M¹ =H; R₅ =3,4-(CH₃ O)₂ C₆ H₃ CH₂ --; Q¹ =6-CH₃ O; Q²=7-CH₃ O; R₃ =3,4-(CH₃ O)₂ C₆ H₃ (CH₂)₂ --; and R₄ =H; m.p. 174°-175°C., M⁺ 601.50.

Example 6: M=H; M¹ =6-CH₃ ; R₅ =H; Q¹ =6-CH₃ O; Q² =7-CH₃ O; R₃=3,4-(CH₃ O)₂ C₆ H₃ (CH₂)₂ --; and R₄ =H; m.p. 72°-76° C., M⁺ 465.0.

Example 7: M, M¹ =H; R₅ =3,4-(CH₃ O)₂ C₆ H₃ CH₂ --; Q¹ =6-CH₃ O; Q²=7-CH₃ O; R₃ =2,3-(CH₃ O)₂ C₆ H₃ (CH₂)₂ --; and R₄ =H; m.p. 69°-72° C.,M⁺ 601.40.

Example 8: M, M¹ =H; R₅ =3,4-(CH₃ O)₂ C₆ H₃ CH₂ --; Q¹ =6-CH₃ O; Q²=7-CH₃ O; R₃ =2-ClC₆ H₄ (CH₂)₂ --; and R₄ =H; m.p. 73°-75° C., M⁺575.30.

Example 9: M, M¹ =H; R₅ =3,4-(CH₃ O)₂ C₆ H₃ CH₂ --; Q¹ =6-CH₃ O; Q²=7-CH₃ O; R₃ =3,4-(CH₂ O₂)C₆ H₃ (CH₂)₂ --; and R₄ =H; m.p. 118°-122° C.,M⁺ 585.3.

Example 10: M, M¹ =H; R₅ =3,4-(CH₃ O)₂ C₆ H₃ CH₂ --; Q¹ =6-CH₃ O; Q²=7-CH₃ O; R₃ =4-CH₃ OC₆ H₄ O(CH₂)₂ --; and R₄ =H; m.p. 160°-162° C., M⁺587.3.

Example 11: M=H; M¹ =6-CH₃ ; R₅ =3,4-(CH₃ O)₂ C₆ H₃ CH₂ --; Q¹ =6-CH₃ O;Q² =7-CH₃ O; and R₃ NR₄ = ##STR15## m.p. 190°-192° C., M⁺ 777.3.

Example 12: M=H; M¹ =6-CH₃ ; R₅ =H; Q¹ =6-CH₃ O; Q² =7-CH₃ O; R₃ =2-ClC₆H₄ (CH₂)₂ --; and R₄ =H; m.p. 174°-177° C., M⁺ 439.0.

Example 13: M=H; M¹ =6-CH₃ ; R₅ =H; Q¹ =6-CH₃ O; Q² =7-CH₃ O; R₃=3,4-(CH₃ O)₂ C₆ H₃ (CH₂)₂ --; and R₄ =H; m.p. 170°-171° C., M⁺ 615.3.

Example 14: M=H; M¹ =6-CH₃ ; R₅ =3,4-(CH₃ O)₂ C₆ H₃ CH₂ ; Q¹ =6-CH₃ O;Q² =7-CH₃ O; R₃ =2,3-(CH₃ O)₂ C₆ H₃ (CH₂)₂ --; and R₄ =H; m.p. 110°-112°C., M⁺ 615.3.

Example 15: M=H; M¹ =6-CH₃ ; R₅ =3,4-(CH₃ O)₂ C₆ H₃ CH₂ ; Q¹ =6-CH₃ O;Q² =7-CH₃ O; R₃ =2-ClC₆ H₄ (CH₂)₂ --; and R₄ =H; m.p. 100°-102° C., M⁺589.3.

Example 16: M=5-CH₃ ; M¹ =6-CH₃ ; R₅ =H; Q=6-CH₃ O; Q² =7-CH₃ O; R₃=3,4-(CH₃ O)₂ C₆ H₃ (CH₂)₂ --; and R₄ =H; m.p. 117°-118° C., M⁺ 478.3.

EXAMPLES 17-20

Employing the procedure of Example 1 and starting with requiredreagents, the following compounds were prepared: ##STR16##

Example 17: M=3,4-(CH₃ O)₂ C₆ H₃ CH₂ --; M¹ =H; R₅ =H; Q¹ =6-CH₃ O; Q²=7-CH₃ O; R₃ =3,4-(CH₃ O)₂ C₆ H₃ (CH₂)₂ --; and R₄ =H; m.p. 89°-91° C.,M⁺ 601.40.

Example 18: M=3,4-(CH₃ O)₂ C₆ H₃ CH₂ --; M¹ =H; R₅ =H; Q¹ =6-CH₃ O; Q²=7-CH₃ O; R₃ =2,3-(CH₃ O)₂ C₆ H₃ (CH₂)₂ --; and R₄ =H; m.p. 89°-91° C.,M⁺ 601.4.

Example 19: M=3,4-(CH₃ O)₂ C₆ H₃ CH₂ --; M¹ =H; R₅ =3,4-(CH₃ O)₂ C₆ H₃CH₂ --; Q¹ =6-CH₃ O; Q² =7-CH₃ O; R₃ =2-ClC₆ H₄ (CH₂)₂ --; and R₄ =H;m.p. 90°-95° C., (free base) M⁺ 725.50.

Example 20: M=H; M¹ =6-Cl; R₅ =H; Q¹ =6-CH₃ O; Q² =7-CH₃ O; R₃ =2-ClC₆H₄ (CH₂)₂ --; and R₄ =H; m.p. (HCl salt) 129°-131° C., M⁺ 459.10.

EXAMPLE 21

2-(1-[3,4-Dimethoxybenzyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)-4-(3,4-dimethoxyphenethylamino)pyrimidinehydrochloride (M and M¹ =H; R₁ R₂ N=3,4-(CH₃ O)₂ C₆ H₃ (CH₂)₂ NH; and R₃R₄N=1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinol-2-yl)

A mixture of 149 mg of 2,4-dichloropyrimidine, 181 mg2-(3,4-dimethoxyphenyl)ethylamine and triethylamine (111 mg) in 2 mL of2-(2-ethoxyethoxy)ethanol was stirred at room temperature for 4 hours.After this period, tetrahydropapaverine hydrochloride (300 mg) andtriethylamine (222 mg) were added and the mixture was heated at 170° C.under nitrogen for 1.5 hours. The precipitate was filtered off and thesolvent was removed under reduced pressure. The residue waschromatographed on silica gel using 2.5% methanol in methylene chloride(V:V) to give 45 mg (7.5%) of solid. This solid was treated with 1Nmethanolic hydrogen chloride to give the title compound as an amorphoussolid: m.p. 48°-51° C., M⁺ 601.

EXAMPLES 22-24

Starting with the appropriate reagents and employing the procedure ofExample 1, the following products were prepared: ##STR17##

Example 22: M and M¹ =H; R₁ =C₆ H₅ CH₂ ; R₂ =CH₃ ; R₃ =3,4-(CH₃ O)₂ C₆H₃ (CH₂)₂ --; and R₄ =H; m.p. 109°-111° C., M⁺ 379.

Example 23: M and M¹ =H; R₁ =C₆ H₅ CH₂ ; R₂ =CH₃ ; R₃ =2,3-(CH₃ O)₂ C₆H₃ (CH₂)₂ --; and R₄ =H; m.p. 128°-129° C., M⁺ 379.

Example 24: M and M¹ =H; R₁ =3,4-(CH₃ O)₂ C₆ H₃ (CH₂)₂ --; R₂ =H; R₃=3,4-(CH₃ O)₂ C₆ H₃ (CH₂)₂ ; and R₄ =H; m.p. 100°-102° C., M⁺ 439.2.

PREPARATION A

Starting with the appropriate reagents and following the procedure ofExample 1C, the following intermediates were prepared: ##STR18##

    __________________________________________________________________________    M             M.sup.1                                                                          R.sub.1 R.sub.2 N      m.p., °C.                      __________________________________________________________________________    H             CH.sub.3                                                                                                138-141                               H             H                                                                                 ##STR19##             149-151                               H             H                                                                                 ##STR20##             146-148                               H             CH.sub.3                                                                          ##STR21##             125-126                                ##STR22##    H                                                                                 ##STR23##             125-127                               H             Cl                                                                                ##STR24##             129-131                               CH.sub.3      CH.sub.3                                                                          ##STR25##             134-136                                ##STR26##    H                                                                                 ##STR27##             145-147                               H             H                                                                                 ##STR28##             oil                                   __________________________________________________________________________

We claim:
 1. A compound of the formula ##STR29## or the pharmaceuticallyacceptable acid addition salt thereof wherein M is hydrogen, alkoxyhaving one to three carbon atoms, alkyl having one to three carbon atomsor benzyl optionally substituted by one or two alkoxy substituents eachhaving one to three carbon atoms, amino, alkylamino having one to threecarbon atoms, dialkylamino having two to six carbon atoms, fluoro,chloro or trifluoromethyl; M¹ is hydrogen, amino, alkylamino having oneto three carbon atoms, dialkylamino having two to six carbon atoms,alkyl having one to three carbon atoms, fluoro or chloro; R₁ is aralkylof the formula ##STR30## wherein n is an integer of 0 or 1, W is O, S ora chemical bond, A is alkylene having one to four carbon atoms, Y and Y¹are each hydrogen, alkyl having one to three carbon atoms, alkoxy havingone to three carbon atoms, fluoro, chloro, trifluoromethyl, amino,alkylamino having one to three carbon atoms or dialkylamino having twoto six carbon atoms and Y and Y¹ when taken together are ethylenedioxyor methylenedioxy; R₂ is hydrogen or alkyl having one to eight carbonatoms; R₁ and R₂ when taken together with the nitrogen atom to whichthey are attached form a moiety of the formula ##STR31## wherein R₅ ishydrogen, alkyl having one to three carbon atoms or dialkoxyphenylalkylsaid alkoxy having one to three carbon atoms and said alkyl having fromone to three carbon atoms, Q and Q¹ are each hydrogen, alkyl having oneto three carbon atoms, alkoxy having one to three carbon atoms, fluoro,chloro, amino, alkylamino having one to three carbon atoms,trifluoromethyl or dialkylamino having two to six carbon atoms and Q andQ¹ taken together are methylenedioxy or ethylenedioxy; R₃ is aralkyl ofthe formula ##STR32## wherein m is an integer of 0 or 1, Z is 0, S or achemical bond, B is alkylene of one to four carbon atoms, X and X¹ areeach hydrogen, alkyl having one to three carbon atoms, alkoxy having oneto three carbon atoms, fluoro, chloro, trifluoromethyl, amino,alkylamino having one to three carbon atoms or dialkylamino having twoto six carbon atoms and X and X¹ taken together are methylenedioxy orethylenedioxy; R₄ is hydrogen or alkyl having one to four carbon atoms;and R₃ and R₄ when taken together with the nitrogen atom to which theyare attached form a moiety of the formula ##STR33## wherein P and P¹ areeach hydrogen, alkyl having one to three carbon atoms, alkoxy having oneto three carbon atoms, fluoro, chloro, trifluoromethyl, amino,alkylamino having one to three carbon atoms or dialkylamino having twoto six carbon atoms, P and P¹ when taken together are methylenedioxy orethylenedioxy and R₆ is hydrogen or dialkoxybenzyl said alkoxy havingone to three carbon atoms.
 2. A compound of claim 1, wherein M¹ ishydrogen or alkyl having one to three carbon atoms, R₁ and R₂ takentogether with the nitrogen atom to which they are attached form a moietyof the formula ##STR34## wherein Q is 6-methoxy, Q¹ is 7-methoxy and R₃and R₄ when taken together with the nitrogen to which they are attachedform a moiety of the formula ##STR35## wherein P is 6-methoxy and P¹ is7-methoxy.
 3. The compound of claim 2, wherein M is hydrogen, M¹ ishydrogen, R₅ is 3,4-dimethoxybenzyl and R₆ is 3,4-dimethoxybenzyl. 4.The compound of claim 2, wherein M is hydrogen, M¹ is hydrogen, R₅ is3,4-dimethoxybenzyl and R₆ is hydrogen.
 5. A compound of claim 1,wherein M is dialkoxybenzyl, M¹ is hydrogen, R₁ and R₂ when takentogether with the nitrogen atom to which they are attached form a moietyof the formula ##STR36## wherein Q is 6-methoxy and Q¹ is 7-methoxy, R₃is aralkyl of the formula ##STR37## wherein m is 0, Z is a chemical bondand B is ethylene and R₄ is hydrogen.
 6. The compound of claim 5,wherein M is 3,4-dimethoxy benzyl, R₅ is hydrogen, X is 2-chloro and X¹is hydrogen.
 7. The compound of claim 5, wherein M is3,4-dimethoxybenzyl, R₅ is hydrogen, X is 3-methoxy and X¹ is 4-methoxy.8. The compound of claim 5, wherein M is 3,4-dimethoxybenzyl, R₅ is3,4-dimethoxybenzyl, X is 2-chloro and X¹ is hydrogen.
 9. A compound ofclaim 1, wherein M is hydrogen, M¹ is hydrogen or alkyl having one tothree carbon atoms, R₃ is aralkyl of the formula ##STR38## wherein m is0, Z is a chemical bond, B is ethylene, R₄ is hydrogen and R₁ and R₂taken together with the nitrogen to which they are attached from amoiety of the formula ##STR39## where Q is 6-methoxy and Q₁ is7-methoxy.
 10. The compound of claim 9, wherein M¹ is methyl, X is3-methoxy, X¹ is 4-methoxy and R₅ is hydrogen.
 11. The compound of claim9, wherein M¹ is hydrogen, X is 2-methoxy, X¹ is 3-methoxy and R₅ is3,4-dimethoxybenzyl.
 12. The compound of claim 9, wherein M¹ ishydrogen, X is 2-chloro, X¹ is hydrogen and R₅ is 3,4-dimethoxybenzyl.13. The compound of claim 9, wherein M¹ is hydrogen, X and X¹ togetherare 3,4-methylenedioxy and R₅ is 3,4-dimethoxybenzyl.
 14. The compoundof claim 9, wherein M¹ is methyl, X is 2-chloro, X¹ is hydrogen and R₅is 3,4-dimethoxybenzyl.